Role of the N-Acetylation Polymorphism in Solithromycin Metabolism

Abstract

Aim: Solithromycin is a new macrolide antibiotic for the potential treatment of bacterial pneumonia. Materials & methods: Solithromycin N-acetylation by human NAT1 and NAT2 was investigated following recombinant expression in yeast and in cryopreserved human hepatocytes from rapid, intermediate and slow acetylators. Results: Solithromycin exhibited over twofold higher affinity for recombinant human NAT2 than NAT1. Apparent maximum velocities for the N-acetylation of solithromycin catalyzed by the NAT2 allozyme associated with rapid acetylators were significantly (p < 0.01) higher than by the NAT2 allozymes associated with slow acetylators. Robust gene dose responses (rapid>intermediate>slow acetylators) were exhibited in cryopreserved human hepatocytes in situ following incubation with 100 μM solithromycin. Conclusion: Solithromycin is N-acetylated by human NAT1 and NAT2 and the role of the NAT2 acetylation polymorphism on solithromycin metabolism may be concentration dependent.

Keywords::

• acetylation polymorphism
• cryopreserved human hepatocytes
• N-acetyltransferase 2
• solithromycin

Financial & competing interests disclosure

Cempra Pharmaceuticals, Inc. (NC, USA), the developer of solithromycin, provided funding, solithromycin and N-acetyl-solithromycin, and suggestions for the manuscript. DW Hein serves as a consultant to Cempra Pharmaceuticals, Inc. and receives payment for services rendered. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Additional information

Funding

Cempra Pharmaceuticals, Inc. (NC, USA), the developer of solithromycin, provided funding, solithromycin and N-acetyl-solithromycin, and suggestions for the manuscript. DW Hein serves as a consultant to Cempra Pharmaceuticals, Inc. and receives payment for services rendered. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed. No writing assistance was utilized in the production of this manuscript.